Method for the manufacture of mixed phosphorothioate esters



METHOD FOR THE MANUFACTURE oF MIXED PHOSPHOROTHIOATE ESTERS Edward J. Tabor, Midland, Micln, assignor to The Dow Chemical Company, Midland, Mich.', 'a corporation of Delaware No Drawing. A rplanes Januar 's, 1m Serial No. 707,669

6 Claims; ((31.260-46-1) The present invention relates to an improved method for the production of mixed phosphorothioate esters and is particularly concerned with a method for the manufacture of O-aryl 0,0-dialkyl phosphorothioates. These compounds are viscous liquids or crystalline solids which are soluble in many organic solvents and of low solubility in water. They are active as parasiticides and are 2,928,864 Patented Mar. 15, 1969 ice 2 be separated by decantation and thereafter washed, as above to obtain the desired product as a liquid residue, The employment of an aqueous solution containing at least 10 percent by weight of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide is essential and critical for the practice of the present invention and the obtaining of the very desirable and high yields of the mixed phosphorothioate esters. In a preferred embodiment of the invention, an aqueous solution adapted to be employed as active toxic constituents of compositions for the control of bacteria, fungi, mites and insect organisms such as aphids, Southern army worms and flies. The compounds are also useful as preservatives for paper, paim na Wood. M I

Several methods of preparing the O-a'ryl 0,0 dia lkyl phosphorothioates are known. In one method'thcfcompounds may be prepared by the reaction of an O-aryl phosphorodichloridothioate and a l, alkali metal aracholate or by the reaction of an'0,0-dialky1phosphorochloridothioate and an alkali metal phenolate. The contacting 'of the reactants .in suchmethods is carried out in an inert organic solvent and at s rerhp rfamrepr from about 15 to 80 C. When operating in accordan e shch methods, the O-aryI 0,0-'d ialkyl phosphorothioates are obtained in yields of about 55 percent or less. In still another method, the mixed phosphorothioate esters may be prepared in'yields of about 75 percentby the reaction of an 0,0-dialkyl phosphorochloridothioate with an aqueous solution of a sodium phenolate in the presence of a copper catalyst. A method for the production of mixed phosphorothioate esters in superior yields would be very desirable.

It is an object of hepisem invention to provide an improved method for the manufacture of mixed phosphorothioate esters. Another object is to provide a method which employs" no catalyst and which may be carried out in water as reaction medium A further object is to provide a method which gives the O-aryl, 0,0-dialkyl phosphorothioates in greateryield andpurity than cent by weight of the alkali metal hydroxide. The reac- *tion takes place smoothly under these described conditions with the production of the desired mixed phosphorotliioate esters in high yields and excellent purity. Upon ,cfomplet idnpr the reaction, the de'sire'd mixed ester, it a solid, may be separated by filtration, successively washed with aqueous alkali metal hydroxide and water ar d airdried. Where therriiied-est'erproduct is a liquid: itm'ay containing from 10 to about 25 percent by weight of the alkali metal hydroxide is employed. A concentration substantially less than 10 percent by. weightrnjaterially reduces the yields of the desired mixed esters and sliduld not be employed. The upper limit of the concentra o of alkali metal hydroxide which may be used varies with the employed alkali metal hydroxide and phenolic coin} pound. In any event, the concentration of th eg alkali rnetal hydroxide must not be so high as to produce; a thickened slurry so that adequate contacting of .the reagents cannot be effected, Under such conditions, the yields ofthe desired mixed phosphorothioate esters materially reduced. Usually adequate contacting may be maintained at concentrations up to about 25 percent by weight of alkali metal hydroxide. A preferred operation comprises employing an aqueous solution containing from 10 to 20 percent by weight of alkali metal hydroxide.

In the practice of the present invention, it is essential that one molecular proportion of the O,Q-di(lower-a1ky l) phosphorochloridothioate is reacted with a mixture containing at least one molecular proportion of each of the alkali metal hydroxide and phenolic compound. Aproportion somewhat smaller than one molecular proportion of each of the phosphorochloridothioate and alkali metal hydroxide materially reduces the yields of the desired mixed ester products and should not be employed. In a preferred method of the present invention, one molecular proportion of the 0,0-di(lower-alkyl) phosphorochloridothioate is reacted with a mixture containing from. L25 to 1.5 molecular proportions of each of the alkali meta 1 hydroxide and phenolic compound. When operatingun; der such conditions, optimum yields of the desired mixed esters are obtained. A larger proportion of the alkali metal hydroxide or phenolic compound may be employed but is undesirable from the standpoint of economy The esterification reaction should be carried ont at temperatures of from 40 to 70 C. andpreferably at the temperature range of from 50 to 60 C. The reaction takes place smoothly under these temperature conditions with theproduction or the desired ester product and alkali metal chloride of reaction. The reaction is somewhat exothermic and the temperature may be controlled by regulating the rate of contacting the reactants and-by external cooling. It is essential that temperatures signifi'cantly above or below the specified range not beemployed for any appreciable period of time as they materially reduce the yield of the desired ester products. A

The rate at which the formation of the desired phosphorothioate esters takes place has been ,found :to vary directly with the employed temperature, thelon'ger periods being employed at the lower temperatures. In general, the reactants may be contacted at as rapid a rate as will permit the control of the temperature within the limits specified. The reaction is generally complete in about one hour.

In carrying out the reaction, the 0,0-di(lower-alkyl) phosphoroch-loridothiate is added portionwise with stirring to a mixture of the alkali metal hydroxide, phenolic compound and Water. In an alternative method opera tion, the order of addition of the reactants is reversed. In either method of operation, the addition is carried out withstirring and at a temperature of from 40 to 70 Example,1.-O (2,4,5 trichlorophenyl) 0,0-dimethyl phosphorothioate I S O CH:

OCH:

.328 grams (2.05 moles) of 0,0-dimethyl phosphorochloridothioate was added portionwise with stirring to a mixture of 106 grams (2.65 moles) of sodium hydroxide,

424 grams (23.5 moles) of water and 494 grams (2.53

moles) of 2,4,5-trichlorophenol. The addition was car- 'ried out at a temperature of from 38 to 51 C. with external cooling and over a period of 25 minutes. Following the addition, the temperature was raised and maintained at 60 C. for a period of 25 minutes. The reaction mixture was then cooled to 45 C. and 600 milliliters of 5 percent sodium hydroxide added with stirring. The reaction mixture was thereafter allowed to cool to room temperature. During the cooling, a solid precipitated which was separated by filtration, washed with water and air-dried. As a result of these operations, there was obtained 585 grams of an O-(2,4,5-trichloro'- phenyl) 0,0-dimethyl phosphorothioate product melting at 40 C. The yield was 91 percent based upon the QQ-dimethyl phosphorochloridothioate starting material.

Example 2.- 2,4,5 trichlorophenyl) 0,0 diethyl 0,0-diethyl phosphorochloridothioate (188.5 grams, 1.0 mole) was added portionwise with stirring to a mixture of 208 grams (11.5 moles) of water, 52 grams (1.3

moles) of sodium hydroxide and 246 grams (1.24 moles) 'of 2,4,5-trichlorophenol. The addition was carried out over a period of 20 minutes and at a temperature of from 40 to 48 C. with external cooling. Following the addition, the temperature was raised to 60 C. and maintained at from 60-70 C. for a period of one hour. The reaction mixture was then cooled to 45 C. and 375 milliliters of percent aqueous sodium hydroxide added with stirring over a period of minutes. When stirring ceased, the liquid product which formed during the reaction was separated from the water layer, washed with water and thereafter dried at a temperature of 69 C. 'and under a vacuum of 13 millimeters. As a result of these operations, there was obtained 312 grams of an 'O-(2,4,5-trichlorophenyl) 0,0-diethyl phosphorothioate product as a pale yellow liquid having a refractive index n/D of 1.5449 at 25 C. The yield was 92 percent based upon the 0,0-diethyl phosphorochloridothioate starting material.

Example 3.--0-(2,4-dichlorophenyl) 0,0-dimethyl phosphorothioate 336 grams (2.1 moles) of 0,0-dimethy1 phosphorochloridothioate was added portionwise with stirring to a mixture of 424 grams (23.5 moles) of water, 106 grams (2.65 moles) of sodium hydroxide and 408 grams (2.5 moles) of 2,4-dichlorophenol. The addition was carried out over a period of 37 minutes and at a temperature of from 40 to 48 C. with external cooling. Following the addition, the temperature was raised and maintained at 60 C. for a period of 30 minutes. The reaction mixture was then cooled to 40 C. and 600 milliliters of 5 percent aqueous sodium hydroxide added with stirring over a period of 5 minutes. When stirring ceased, the liquid product which formed during the reaction was separated from the water layer, washed with water and dried at a temperature of 60 -70 C. and a reduced prasure of 12 millimeters. As a result of these operations, there was obtained 500 grams of an 0-(2,4-dichlorophenyl) 0,0-dimethyl phosphorothioate product as a viscousliquid having a refractive index n/D of 1.5496 at 25 C. The yield was 87 percent based upon the 0,0-dimethyl phosphorochloridothioate starting material.

Example 4.-0-(2-chloro-4-tertiarybulylphenyl) 0,0-di- V methyl phosphorothioate 73 grams (0.45 mole) of 0,0-dimethyl phosphorochloridothioate was added portionwise with stirring to a mixture of 94 grams (5.2 moles) of water, 32 grams (0.57 mole) of potassium hydroxide and grams (0.54 mole) of 2-chloro-4-tertiarybutyl phenol. The addition was carried out at a temperature of from 50 to 60 C. with external cooling and over a period of 22 minutes. Following the addition, the temperature was maintained at 60-63 C. for a period of 15 minutes. The reaction mixture was then cooled to 48 C. and milliliters of 5 percent aqueous potassium hydroxide added over a period of 5 minutes with stirring. When stirring ceased, the liquid product which formed during the reaction was separated from the water layer, washed with water, filtered and dried under reduced pressure at a temperature of 60 C. As a result of these operations, there was obtained 120 grams of an O-(2-chloro-4-tertiarybutylphenyl) 0,0-dimethyl phosphorothioate product as a viscous liquid having a refractive index n/D of 1.5278 at 25 C. The yield was 89.2 percent based upon the 0,0- dimethyl phosphorochloridothioate starting material.

Example 5.--O-(j3-naphthyl) 0,0-dimethyl phosphorothioate OCH:

164 grams (1.0 mole) of 0,0-dimethyl phosphorochloridothioate was added portionwise with stirring to a mixture of 212 grams (11.8 moles) of water, 53 grams (1.32 moles) of sodium hydroxide and grams (1.25 moles) of p-naphthol. The addition was carried out over a period of 16 minutes and at a temperature of from 51 to 55 C. with external cooling. Following the addition, the temperature was raised and maintained at 60 C. for a period of 15 minutes. The reaction mixture was then cooled to 45 C. and 375 milliliters of 5 percent aqueous sodium hydroxide added with stirring over a period of 10 minutes. When stirring ceased, the liquid product which had formedduring the reaction was separated from the water layer, washed with water and dried at a temperature of 74 C. and under a vacuum of 12 millimeters. As a result of these operations, there was obtained 237 grams of an O-(B-naphthyl) 0,0-dirnethyl phosphorothioate product as a brown, viscous liquid having a refractive index n/D of 1.5936 at 25 C. The yield was 88.5 percent based upon the 0,0-dimethyl phose l qthi a e s ar i g material.

Example'd' '7 0,0-dimethyl phosphorochloridothioate (65.5 grams, 0.41 mole) is added to a mixture of 193 grams (10.7 moles) of water, 21.5 grams (0.53 mole) of sodium hydroxide. and 100 grams (0.5 mole) of 2,4,5-trichlorophenol to produce a reaction system containing one molecular proportion of the phosphorochloridothioate per 1.25 molecular proportions of trichlorophenol and 1.3 molecular proportions of sodium hydroxide which is employed as a 10 percent by weight aqueous solution. In a similar manner, other reaction systems are prepared in which the molar ratios of the reactants are kept constant but the concentration of the sodium hydroxide solution employed is 15 and 20 percent by weight of aqueous solution.

In each of the above systems, the phosphorochloridothioate is added portionwise with stirring to the aqueous mixture of sodium hydroxide and trichlorophenol in 15 minutes and at a temperature of from 40 to 45 C. Following the addition, the temperature is raised and maintained at 60 C. for one hour. Thereafter, the liquid product which formed is decanted from the water layer, dried at 6070 C. under a reduced pressure of 12 millimeters and weighed. The yields of O-(2,4,5-trichlorophenyl) 0,0-dimethyl phosphorothioate for the various systems are set forth in the following table, the yields being based upon the 0,0-dimethyl phosphorochloridothioate starting material:

Mole Ratio of Reactants Concentration Percent; Yield of N aOH Soluof (2 tlon Based trichloro- 0,0-Dimethyl 2,4,5Triupon Weight phenyl) Phosphorochloroof Water 0,0-dimethyl chloridothioat/e phenol Employed Phosphoro thioate vention may be employed to obtain the very desirable and improved yields of the following mixed phosphorothioate esters:

O-(4-benzylphenyl) 0,0-dipropyl phosphorothioate O-(Z-methoxyphenyl) 0,0-dibutyl phosphorothioate O-(2-ethyl-4-bromophenyl) 0,0-diamyl phosphorothioate O-(anthracyl) 0,0-diisopropyl phosphorothioate O-(4-cyclohexylphenyl) 0,0-diethyl phosphorothioate O-(2-ethoxy-4-chlorophenyl) 0,0-ditertiarybutyl phosphorothioate O-(2-biphenylyl) 0,0-diamyl phosphorothioate O-(2-bromo-4-propoxyphenyl) 0,0-dimethyl phosphorothioate O-(2-bromo-4-chlorophenyl) 0,0-dipropyl phosphorothioate O-(4-tertiarybutylphenyl) 0,0-diethyl phosphorothioate 0-(2-chlorophenyl) 0,0-disecondarybutyl phosphorothi-.

oate O-(3,4-dibromophenyl) 0,0-diamyl phosphorothioate O-(metacresyl) 0,0-diisopropyl phosphorothioate C-(2-ethylpheny1) 0,0-diethy1 phosphorothioate The 0,0-.di(lower-alky-l)v phosphoroehloridothioates employed as starting materials in the present invention may be prepared by the reaction of one molecular pro.- portion of phosphorus thiochloride with two molecular proportions of a suitable sodium alkoxide in the corresponding alcohol. The reaction is somewhat exothermic and is carried out at a temperature of from .10 to 30 C. Upon completion of the reaction, the solvent may be removed by evaporation to obtain the desired O,Q dialkyl phosphorochloridothioate as a liquid residue,

The preferred embodiments of the present invention include the manufacture of the O-aryl 0,0,-di(loweralkyl) phosphorothioates having the formula SOX wherein R represents a phenyl radical unsubstituted or substituted by one or more substituents such as chlorine, bromine, lower alkyl, lower alkoxy, phenyl, benzyl or cyclohexyl and X represents lower alkyl. The term lower alkyl refers to the radicals containing from 1 to 5 carbon atoms, inclusive.

1 claim:

1. A method for the manufacture of a mixed phosphorothioate ester which comprises reacting in the absence of a catalyst and at a temperature of from 40 to C. one molecular proportion of an 0,0-di(loweralkyl) phosphorochloridothioate with a mixture comprising at least one molecular proportion of each of an alkali metal hydroxide and a phenolic compound, said alkali metal hydroxide being employed in the form of an aqueous solution containing at least 10 percent by weight of the alkali metal hydroxide, and said phenolic compound having the formula ROH wherein R represents a phenyl radical whose nucleus may be substituted with a radical selected from the group consisting of chlorine, bromine, lower alkyl,, lower alkoxy, cyclohexyl, benzyl and phenyl.

2. A method for the manufacture of O-(2,4,5-trichlorophenyl) 0,0-dimethyl phosphorothioate which comprises reacting in the absence of a catalyst and at a temperature of from 40 to 70 C. one molecular proportion of 0,0- dimethyl phosphorochloridothioate with a mixture comprising at least one molecular proportion of each of 2,4,5- trichlorophenol and an alkali metal hydroxide, said alkali metal hydroxidebeing employed in the form of an aqueous solution containing at least 10 percent by weight of the alkali metal hydroxide.

3. A method for the manufacture of O-(2,4-dichlorophenyl) O,'O-dimethyl phosphorothioate which comprises reacting in the absence of a catalyst and at a temperature of from 40 to 70 C. one molecular proportion of 0,0- dimethyl phosphorochloridothioatewith a mixture comprising at least one molecular proportion of each of 2,4- dichlorophenol and an alkali metal hydroxide, said alkali metal hydroxide being employed in the form of an aqueous solution containing at least 10 percent by weight of the alkali metal hydroxide.

4. A method for the manufacture of 0-(2-chloro-4- tertiary butylphenyl) 0,0 dimethyl phosphorothioate which comprises reacting in the absence of a catalyst and at a temperature of from 40 to 70 C. one molecular proportion of 0,0-dimethyl phosphorochloridothioate with a mixture comprising at least one molecular proportion of each of 2-chloro-4-tertiarybutyl phenol and an alkali metal hydroxide, said alkali metal hydroxide being employed in the form of an aqueous solution containing at 5. A method for the manufacture of O-(2,4,5-trichlorophenyl) 0,0-diethyl phosphorothioate which comprises reacting in the absence of a catalyst and at a temperature of from 40 to 70 C. one molecular proportion of 0,0- diethyl phosphorochloridothioate with a mixture comprising at least one molecular proportion of each of 2,4,5-

trichlorophenol and an alkali metal hydroxide, said alkali 7 metal hydroxide being employed in the form of an aqueous solution containing at least 10 percent by weight of the alkali metal hydroxide.

6. A method for the manufacture of 0-(;3-naphthy1) 0,0-dimethyl phosphorothioate which comprises reacting in the absence of a catalyst and at a temperature of from 40 to 70 C. one molecular proportion of 0,0-dimethyl phosphorochloridothioate with a mixture comprising at least one molecular proportion of each of fi-naphthol and an alkali metal hydroxide, said alkali metal hydroxide being employed in the form of an aqueous solution con- 8 taining at least 10 percent by weight of the alkali metal hydroxide. I

References Cited in the fi le of this patent I UNITED STATES PATENTS Young et al Oct. 26, 1954 Boyer Sept. 4, 1956 OTHER REFERENCES 

1. A METHOD FOR THE MANUFACTURE OF A MIXTURE PHOSPHOROTHIOATE ESTER WHICH COMPRISES REACTING IN THE ABSENCE OF A CATALYST AND AT A TEMPERATURE OF FROM 40* TO 70*C. ONE MOLECULAR PROPORTION OF AN O,O-DI(LOWERALKYL) PHOSPHOROCHLORIDOTHIOATE WITH A MIXTURE COMPRISING AT LEAST ONE MOLECULAR PORTION OF EACH OF AN ALKALI METAL HYDROXIDE AND A PHENOLIC COMPOUND, SAID ALKALI METAL HYDROXIDE BEING EMPLOYED IN THE FORM OF AN AQUEOUS SOLUTION CONTAINING AT LEAST 10 PERCENT BY WEIGHT OF THE ALKALI METAL HYDROXIDE, AND SAID PHENOIC COMPOUND HAVING THE FORMULA ROH WHEREIN R REPRESENTS A PHENYL RADICAL WHOSE NUCLEUS MAY BE SUBSTITUTED WITH A RADICAL SELECTED FROM THE GROUP CONSISTING OF CHLORINE, BROMINE, LOWER ALKYL, LOWER ALKOXY, CYCLHEXYL, BENZYL AND PHENYL. 